Research ArticleThe Clinical Efficacy of Phytochemical Medicines ContainingTanshinol and Ligustrazine in the Treatment of Stable Angina:A Systematic Review and Meta-Analysis

Li Gao ,1,2 Tong Wu ,1 Juan Wang ,1 Zhuoran Xiao ,1 Chunhua Jia ,1

and Wei Wang 1

1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China2St Michael’s Hospital, University of Toronto, Toronto, M5B 1W8, Canada

Correspondence should be addressed to Chunhua Jia; chjia11@163.com and Wei Wang; wangwei@bucm.edu.cn

Received 12 May 2020; Revised 22 November 2020; Accepted 21 January 2021; Published 3 February 2021

Academic Editor: Sai-Wang Seto

Copyright © 2021 Li Gao et al. ,is is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Phytochemical medicines containing tanshinol and ligustrazine are commonly used in the treatment of stable angina inChina, but their clinical effectiveness and risk have not been adequately assessed. In this paper, we conducted a systematic review andmeta-analysis to evaluate the clinical efficacy. Methods. Relevant randomized controlled trials (RCTs) of phytochemical medicinescontaining tanshinol and ligustrazine in the treatment of stable angina were searched in electronic databases. ,e search date was up toMarch 31, 2020, and the languages of the RCTswere limited to English andChinese.Results. A total of 28 studies, including 2518 patients,were included in the meta-analysis. It was shown that the adjunctive therapy of phytochemical medicines containing tanshinol andligustrazine was better than the conventional therapies in the improvement of stable angina according to the clinical efficacy insymptoms (n� 2518, RR� 1.24, 95% CI: 1.20 to 1.29, P< 0.01) and clinical efficacy in electrocardiography (n� 1766, RR� 1.29, 95%CI:1.19 to 1.40, P< 0.01). Conclusion. ,e meta-analysis supported the use of phytochemical medicines containing tanshinol and lig-ustrazine in the treatment of stable angina. However, quality of the evidence for this finding was low due to a high risk of bias in theincluded studies. ,erefore, well-designed RCTs are still needed to further evaluate the efficacy.

1. Introduction

Stable angina is caused by fixed blockages in coronary ar-teries [1]. It typically occurs during activities, and the mainsymptoms are chest tightness and shortness of breath, whichcan be alleviated after a rest or administration of sublingualnitroglycerin [2–4]. Stable angina is a chronic coronarydisease compared with unstable angina; however, it seriouslyaffects patients’ lives, such as restricting daily activities [5].,en, the treatment aims to reduce morbidity and improvesymptoms.

Currently, the main treatment of stable angina ismedicine, such as nitroglycerin, beta-blockers, or calciumchannel blockers, which focus on decreasing heart’s work-load and prevent episodes [6–9]. In China, phytochemicalmedicines are also used by many physicians. For example,

Shao et al. [10] conducted a meta-analysis to assess theefficacy of danshen injection (main component: salvianic aidA) in the treatment of angina pectoris and concluded that itis more effective than antianginal agents alone. Yu et al. [11]andWang et al. [12] conducted randomized controlled trialsin the treatment of stable angina, respectively, and foundthat xinxuekang capsule (main component: steroidal sa-ponins) had a better efficacy compared with danshen tablets.In addition, for the treatment of unstable angina, manyresearchers have supported different phytochemical medi-cines, such as puerarin injection [13], safflower yellow in-jection [14], and danshen chuanxiongqin injection [15].

In these phytochemical medicines, tanshinol and lig-ustrazine are the commonly used components. Tanshinol isalso named salvianic aid A, with a molecular formulaC9H10O5 [16]. Ligustrazine’s molecular formula is C8H12N2

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2021, Article ID 8616413, 10 pageshttps://doi.org/10.1155/2021/8616413

[17]. Tanshinol has antioxidant capacity [18]; it can at-tenuate oxidative stress by decreasing the expressions ofFoxO3a signaling [19] and improve cardiovascular injuryby scavenging reactive oxygen species [20]. In addition,tanshinol can attenuate endothelial cell apoptosis, whichhelps reduce the aortic atherosclerotic lesion area [21].Ligustrazine has effects on calcium channels; the researchof Ren et al. [22] showed that ligustrazine could signifi-cantly suppress calcium transient and contraction inrabbits. It was also reported that the ligustrazine exhibits ananti-inflammatory effect; as Guo et al. described, the salvialigustrazine injection could decrease high-sensitivityC-reactive protein and interleukin-6 levels [17, 23]. Lig-ustrazine was also found to suppress acid-sensing ionchannels and reduce ischemia-induced infarct size in ratswith angina [24]. ,e combination of tanshinol and lig-ustrazine has efficacy in dilating coronary arteries, reducingblood viscosity, promoting blood circulation, and re-moving blood stasis through synergistic action [25–27]. Yeet al. [28] investigated the anti-inflammatory effect ofdanshen, chuanxiong, and their combination and foundthat their combination has a dual anti-inflammatory effecton macrophages and endothelial cells. All these findingsprovide a biological basis of tanshinol and ligustrazine inthe treatment of angina.

Tanshinol and ligustrazine are the main compounds ofdanshen and chuanxiong. ,ere are several phytochemicalmedicines whose main components are tanshinol and lig-ustrazine, such as danshen chuanxiongqin injection, guan-xinning injection, and shenxiong glucose injection. Severalsystematic reviews have been conducted to evaluate the ef-ficacy of these medicines in the treatment of angina pectoris.Jia et al. [29] analyzed eligible RCTs using guanxinning in-jection, Zhang et al. [15] assessed danshen chuanxiongqininjection in treating unstable angina pectoris, and Liu andDing [30] assessed shenxiong glucose injection in the treat-ment of unstable angina pectoris. In addition, many ran-domized controlled trials have been published to support theuse of danshen and chuanxiongqin in the treatment of stableangina. However, in the treatment of stable angina, no rel-evant meta-analysis has been conducted to assess the clinicalefficacy or the risk of phytochemical medicines containingtanshinol and ligustrazine. ,erefore, in this study, a meta-analysis was conducted to evaluate the efficacy of phyto-chemical medicines in the treatment of stable angina.

2. Methods

,e protocol of this study was registered in PROSPEROwiththe registration number CRD42018105921.

2.1. Database and Search Strategies. ,e following electronicdatabases were searched by two independent reviewers (GaoL. and Wang J.): Web of Science, Cochrane Library,PubMed, Chinese Biomedical Literature Database, ChineseNational Knowledge Infrastructure, Chinese ScientificJournal Database, and Wanfang Database. ,e search datewas up to March 31, 2020, and the languages of the

publications were limited to English and Chinese. ,e fol-lowing search terms were used: (tanshinol OR salvianic acidA OR β-(3,4-dihydroxyphenyl) lactic acid OR danshensuOR danshen OR radix salvia OR salvia miltiorrhiza) AND(ligustrazine OR chuanxiong OR chuanxiongzine OR tet-ramethylpyrazine) AND (stable angina OR angina OR an-gina pectoris OR stenocardia OR angor pectoris) AND(randomized controlled trial).

2.2. Inclusion Criteria. ,e included studies must be RCTs.

Participants: patients who were diagnosed with stableangina were included. ,e stable angina was diagnosedaccording to the criteria [31, 32], with tests such aselectrocardiography (ECG), exercise ECG, and symp-toms of the patients.Interventions: interventions using phytochemicalmedicines containing tanshinol and ligustrazine as amain treatment were chosen. ,e dosages of tanshinoland ligustrazine should be described specifically.Comparators: the control groups received conventionaltreatments, such as taking medicines to treat andprevent angina attacks. Placeboes were also included.Outcomes: the primary outcome was the clinical effi-cacy in symptoms and ECG; the secondary outcome isadverse event.

2.3. Exclusion Criteria. ,e exclusion criteria in the meta-analysis included (a) non-RCTs, case studies, experiencesummaries, animal experiments, and unpublished or re-peated studies; (b) studies that used herbal medicines as themain intervention in addition to tanshinol and ligustrazine;(c) studies that used acupuncture or cupping as combinedtherapies; (d) patients who were identified as unstable an-gina; and (e) patients who have complications of heartfailure, diabetes, stroke, or some other serious organicdiseases.

2.4. Data Extraction andQuality Assessment. Four reviewers(Gao L, Wu T, Jia C, and Xiao Z) independently performedthe data extraction and quality assessments. Meta-analysiswas conducted using RevMan 5.3 software, and the risk ofbias was assessed according to the Cochrane handbook [33].Any disagreement was resolved by discussions among allreviewers.

3. Results

3.1.Description of the Included Studies. In this meta-analysis,1613 studies were identified through database searching. But500 repeated studies were excluded and 882 irrelevantstudies were excluded through title and abstract reviewing.,e full texts of 231 studies were assessed and 203 studieswere excluded, including 75 studies that used some otherherbal medicines in addition to tanshinol and ligustrazine inthe intervention group, 96 studies included patients withunstable angina, 2 study lacked data on the dosages of

2 Evidence-Based Complementary and Alternative Medicine

tanshinol and ligustrazine, 1 study lacked data to judge theefficacy, and 29 studies had patients with complications. Atlast, a total of 28 studies [34–61] were included in the meta-analysis. ,e screening process is summarized in a PRISMAflow diagram (Figure 1).

Details of the 28 studies are summarized in Table 1.,ere were 2518 patients in total, including 1276 patients inthe intervention group and 1242 patients in the controlgroup. Sample sizes of the studies were small, and only 8studies had sample sizes greater than 100 patients. ,eyoungest patient in these studies was 46 years old, whilemost of the studies reported patients older than 60 years old.Many patients had a long course of the disease, and thelongest course was 25 years. In the control group, con-ventional treatments were used, such as nitroglycerin, beta-blockers, and calcium channel blockers. No study used aplacebo. In the intervention group, phytochemical medi-cines containing tanshinol and ligustrazine were used basedon the control group, except that one study that used aphytochemical medicine containing tanshinol and lig-ustrazine alone. ,e uses of tanshinol and ligustrazine werein different forms, 21 studies used danshen chuanxiongqininjection (DCI), 5 studies used shenxiong glucose injection(SGI), and 2 studies used danshen injection (DI) combinedwith ligustrazine injection (LI). ,e nature of constituents isbotanical. 1ml DCI contains 0.4mg tanshinol and 20mgligustrazine, 1ml SGI contains 0.2mg tanshinol and 1mgligustrazine, and 1ml DI contains 0.2mg tanshinol. Detailsof the constituents of the 28 included studies are shown inAppendix table (available here). ,e treatment durationlasted from 7 days to 30 days. All the studies used clinicalefficacy in symptoms as the main outcome, and 18 studiesused clinical efficacy in ECG.

3.2. Risk of Bias. ,e risk of bias was high in the includedstudies (Figure 2). All the studies were described usingrandomization, but only five of these studies[35, 38, 44, 47, 55] reported using an appropriate method ofrandom sequence generation. None of the studies describedthe method for allocation concealment, blinding of partic-ipants and personnel, and blinding of the outcomeassessment.

3.3.OutcomeMeasurements. ,e outcome measurements ofthe included studies include clinical efficacy in symptoms,clinical efficacy in ECG, and adverse events.

3.3.1. Clinical Efficacy in Symptoms. ,e criteria for clinicalefficacy in symptoms are defined as follows [62]: effective(the frequency of angina or the amount of nitroglycerineused is reduced by more than 50%) and no effect (thefrequency of angina or the amount of nitroglycerine used isreduced by less than 50%).

All the studies showed that phytochemical medicinescontaining tanshinol and ligustrazine have better clinicalefficacy in symptoms. Since low heterogeneity was observedin the meta-analysis (I2 � 43%, which is lower than 50%), a

model of fixed effects was used to calculate the pooled es-timation with an analysis of the dichotomous data usingrelative risk (RR), including 95% confidence intervals (CIs).,e total meta-analysis showed favorable effects of phyto-chemical medicines on clinical efficacy (n� 2518, RR� 1.24,95% CI: 1.20 to 1.29, P< 0.01) compared with the controlgroup (Figure 3).

3.3.2. Clinical Efficacy in ECG. ,e criteria for clinical ef-ficacy in ECG are defined as follows [62]: effective (recoveryof ST-segment depression is more than 0.05mV, or am-plitude of the inverted Twave reduces more than 50%, or theshape of T wave changes from flat to upright) and no effect(no improvements in ECG compared with before).

Since high heterogeneity was observed in the meta-analysis (I2 � 64%, which is higher than 50%), a model ofrandom effects was used. ,e total meta-analysis showedfavorable effects of phytochemical medicines on ECG(n� 1766, RR� 1.29, 95% CI: 1.19 to 1.40, P< 0.01) com-pared with the control group (Figure 4).

3.3.3. Adverse Events (AEs). Only 10 studies reported AEs,of which 7 studies [35, 39, 40, 49, 54, 56, 59] reported thatthere were no AEs. In the other three studies [38, 42, 55], twostudies reported AEs in the intervention group, including 2cases of skin rash, 1 case of epigastric discomfort, 1 case ofinsomnia, and 1 case of tiredness, and three studies reportedAEs in the control group, including 2 cases of nausea, 1 caseof stomachache, 1 case of dizziness, 2 cases of skin rash, 4cases of epigastric discomfort, 3 cases of insomnia, and 3cases of tiredness. Other studies did not report AEs.

4. Discussion

Currently, phytochemical medicines containing tanshinoland ligustrazine have been widely utilized by physicians totreat stable angina in China. However, it is controversialsince there was no systematic review to assess the therapy’sclinical efficacy. ,erefore, this meta-analysis aimed toevaluate the efficacy or risk of phytochemical medicines inthe treatment of stable angina.

In this meta-analysis, DCI and SGI were used by moststudies. Both DCI and SGI consist of tanshinol and lig-ustrazine. As reported, DCI and SGI have been studied in thetreatment of acute myocardial infarction [63], myocardialischemia/reperfusion injury [64], and focal cerebral ische-mia [65]. In the theory of traditional Chinese medicine,angina pectoris should be treated by supplementing qi andactivating blood circulation. Tanshinol and ligustrazine areextracted from danshen and chuanxiong, which are twocommonly used herbs in the treatment of cardiac diseases inChina.

Tanshinol is the drug used for promoting blood cir-culation and removing blood stasis, which can improvecardiac function by increasing coronary blood flow andslowing the heart rate down [66]. Clinical practice hasproved that salvia has a curative effect on myocardialhypoxia caused by myocardial infarction, and it plays a role

Evidence-Based Complementary and Alternative Medicine 3

Records identified through databasesearching(n = 1613)

Scre

enin

gIn

clud

edEl

igib

ility

Iden

tifica

tion Additional records identified

through other sources(n = 0)

Records a�er duplicates removed(n = 1113)

Records excludedthrough reviewing title

and abstract(n = 882)

Records screened(n = 1113)

Full-text articles assessedfor eligibility

(n = 231)

Full-text articles excluded,with reasons (n = 203)

Studies included inqualitative synthesis

(n = 28)

Studies included inquantitative synthesis

(meta-analysis)(n = 28)

Intervention group usedsome other herbalmedicines in addition todanshensu andligustrazine (n = 75)Including patients withunstable angina (n = 96)Lack of data (n = 3)Patients havecomplications (n = 29)

(i)

(ii)

(iii)(iv)

Figure 1: PRISMA flow diagram of the screening process.

Table 1: Details of the 28 included studies on phytochemical medicines containing tanshinol and ligustrazine in the treatment of stableangina.

Study Sample size Age (years)Course ofdisease(years)

Intervention group Control groupTreatmentduration(days)

Mainoutcomes

Cao andWang[34]

118 (59/59) 63.0± 14.061.5± 14.5 NR DCI (10ml) + TCR

Nifedipine 30–60mg/d;metoprolol 100–200mg/d;aspirin 100–300mg/d;

nitroglycerin when necessary

14 CES +ECG

Chen[35] 100 (50/50) 57.24± 9.64 NR DCI (10ml)

Aspirin 100mg/d; atorvastatin20mg/d; trimetazidine 60mg/

d; nitroglycerin 10mg/d7 CES

Ding[36] 60 (30/30) 56–72 NR DCI (10ml) + TCR Nitroglycerin 10 CES

Han [37] 60 (30/30) 64.9± 5.8965.7± 7.93 NR DCI (10ml) + TCR Nitrates; aspirin; calcium

channel blockers 14 CES

He andLi [38] 70 (35/35) 48.2± 2.1 NR DCI (10ml) + TCR Aspirin; nitrates 14 CES

Hu [39] 58 (30/28) 60± 859± 9 NR DCI (10ml) + TCR Nitrates; beta-blockers; calcium

channel blockers; aspirin 14 CES +ECG

Hua et al.[40] 70 (35/35) 64.7± 8.4

63.3± 8.3 0.5–10 DCI (10ml) + TCR

Isosorbide mononitrate 25mg/d; quinapril 10mg/d;

metoprolol 50mg/d; aspirin100mg/d

14 CES +ECG

4 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued.

Study Sample size Age (years)Course ofdisease(years)

Intervention group Control groupTreatmentduration(days)

Mainoutcomes

Jia [41] 76 (38/38) 62.04± 2.1561.92± 2.13 NR DCI (10ml) + TCR

Aspirin 100mg/d; atorvastatin20mg/d; trimetazidine 60mg/d; isosorbide mononitrate

40mg/d

7 CES

Lan [42] 216 (116/100)

57.6± 4.658.1± 5.2

7.62± 3.878.91± 4.28 DCI (10ml) + TCR Nitrates; beta-blockers; calcium

channel blockers; aspirin 14 CES +ECG

Li et al.[43] 80 (40/40) 67.3± 6.20 3.5± 1.6 DCI (10ml) + TCR

Isosorbide mononitrate 40mg/d; metoprolol 47.5mg/d;

aspirin 100mg/d; trimetazidine60mg/d

14 CES +ECG

Li and Li[44] 80 (40/40) 58.93± 2.07

58.42± 2.314.45± 1.434.37± 1.52 DCI (10ml) + TCR

Aspirin 100mg/d; atorvastatin20mg/d; trimetazidine 60mg/d; isosorbide mononitrate

40mg/d

7 CES

Li [45] 216 (108/108) 64.7± 4.8 10.6± 1.2 DCI (10ml) + TCR Aspirin; calcium channel

blockers; beta-blockers; nitrates 14 CES +ECG

Liu andLi [46] 60 (30/30) 63.7± 7.7

64.9± 9.4 NR SGI (100ml) + TCRNitrates; aspirin; beta-blockers;calcium channel blockers; ACE

inhibitors; ARBs14 CES

Ma et al.[47] 80 (40/40) NR NR DCI (10ml) + TCR Nitrates; beta-blockers; calcium

channel blockers; aspirin 14 CES +ECG

Ma et al.[48] 104 (52/52) 63.74± 11.83

62.34± 10.63 NR SGI (100ml) + TCR

Aspirin 100mg/d; isosorbidemononitrate 40mg/d;metoprolol 50mg/d;atorvastatin 20mg/d

14 CES

Ou [49] 60 (30/30) 60.33± 10.0461.21± 9.36

0.08–120.16–13 SGI (100ml) + TCR

Nitrates; beta-blockers; calciumchannel blockers; antiplatelet

drug14 CES +ECG

Pang andLiu [50] 64 (32/32) 77.2± 5.6 6–20 SGI (200ml) + TCR

Antiplatelet drug; beta-blockers; statins; ACE

inhibitors; ARBs; nitrates; lipid-lowering drug; hypotensor;nitroglycerin; isosorbidemononitrate 20mg/d

14 CES +ECG

Sun [51] 80 (40/40) 72.3± 0.271.9± 0.4

5.2± 0.65.1± 0.4 DCI (5ml) + TCR

Antiplatelet drug; thrombolyticdrug; lipid-lowering drug;hypotensor; digoxin when

necessary

30 CES +ECG

Tian [52] 62 (32/30) 61.68± 10.9860.39± 9.76 NR DCI (20ml) + TCR Nitrates; calcium channel

blockers 14 CES

WangandWang[54]

62 (31/31) 46–58 3–18 DI (20ml) + LI(80mg) +TCR

Nitrates; beta-blockers; calciumchannel blockers 14 CES +ECG

Wangand Lian[53]

105 (56/49) 51–75 1.6–25 DCI (10ml) + TCR Nitrates; beta-blockers; calciumchannel blockers; aspirin 14 CES +ECG

Xi [55] 80 (40/40) 59.3± 6.462.4± 5.3

5.9± 0.64.8± 0.8 DCI (10ml) + TCR Aspirin; atorvastatin;

nitroglycerin 14 CES

Xie andZhu [56] 104 (52/52) 51–79 1.6–25 DI (20–30ml) + LI

(40–80mg) +TCRNitrates; beta-blockers; calcium

channel blockers; aspirin 14 CES +ECG

Xing [57] 100 (50/50) 66.2± 5.60 2.8± 1.8 DCI (10ml) + TCR Isosorbide mononitrate 40mg/d; aspirin 100mg/d 14 CES +ECG

XiongandWang[58]

85 (46/39) 52–71 1.6–25 DCI (10ml) + TCR Nitrates; beta-blockers; calciumchannel blockers; aspirin 14 CES +ECG

Evidence-Based Complementary and Alternative Medicine 5

in anticoagulation by dilating peripheral vessels to reduceblood pressure and improving cAMP (cyclic adenosinemonophosphate) in cells [67, 68]. Ligustrazine is a kind ofactive alkaloid, which is effective to dilate coronary arteriesand reduce coronary resistance. Ligustrazine is efficient inincreasing coronary blood flow and improving myocardialoxygen supply, making it commonly to be used to inhibitplatelet aggregation and depolymerize the aggregated

platelets [69, 70]. In the treatment of cardiac diseases,tanshinol and ligustrazine can promote blood circulation,dilate coronary arteries, and inhibit platelet aggregation[29, 71], which provides a rationale in the treatment ofstable angina.

Heterogeneity in this meta-analysis was moderate, withclinical efficacy in symptoms of I2 � 43%, and clinical efficacyin ECG of I2 � 64%.,e reasons for this may be that different

Unclear risk of biasLow risk of bias

High risk of bias

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

0 25 50(%)

75 100

(a)

Random sequence generation (selection bias)Allocation concealment (selection bias)Blinding of participants and personnel (performance bias)Blinding of outcome assessment (detection bias)Incomplete outcome data (attrition bias)Selective reporting (reporting bias)Other bias

Cao

Y (2

017)

Chen

X (2

017)

Din

g X

(201

6)H

an J

(201

6)H

e L (2

017)

Hua

Z (2

014)

Hu

L (2

012)

Jia Z

(201

7)La

n D

(201

5)Li

J (2

012)

Li P

(201

7)Li

Q (2

015)

Liu

L (2

011)

Ma C

(201

3)M

a T (2

016)

Ou

M (2

008)

Pang

G (2

010)

Sun

D (2

018)

Tian

H (2

008)

Wan

g X

(200

8)W

ang

X (2

010)

Xie D

(200

6)Xi

H (2

017)

Xing

B (2

013)

Xion

g B

(200

9)Xu

G (2

012)

Yu M

(201

6)Zh

ang

W (2

018)

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+

++

++

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Figure 2: Risk of bias graph: (a) risk of bias in all included studies; (b) risk of bias summary.

Table 1: Continued.

Study Sample size Age (years)Course ofdisease(years)

Intervention group Control groupTreatmentduration(days)

Mainoutcomes

Xu andQin [59] 84 (42/42) 56.14± 7.40

51.20± 7.301–132–12 DCI (10ml) + TCR Nitrates; aspirin; beta-blockers;

nitroglycerin when necessary 14 CES +ECG

Yu andFang[60]

94 (47/47) NR NR DCI(5–10ml) + TCR

Antiplatelet drug; thrombolyticdrug; lipid-lowering drug;hypotensor; digoxin when

necessary

20 CES +ECG

Zhang[61] 90 (45/45) 68.21± 9.26

68.52± 9.39 NR SGI (200ml) + TCR

Antiplatelet drug;anticoagulant; ACE inhibitors;beta-blockers; calcium channel

blockers; statins; nitrates

10–14 CES +ECG

NR: not reported; DCI: danshen chuanxiongqin injection; SGI: shenxiong glucose injection; DI: danshen injection; LI: ligustrazine injection; GI: guanxinninginjection; TCR: treatments in the control group; ACE: angiotensin-converting enzyme; ARBs: angiotensin receptor blockers; CES: clinical efficacy insymptoms; ECG: electrocardiography.

6 Evidence-Based Complementary and Alternative Medicine

Study or subgroup Experimental Control Risk ratioM-H, random, 95% CI

Risk ratio

Cao Y (2017)

0.5 0.7Favours (control) Favours (experimental)

1 21.5

Hua Z (2014)Hu L (2012)

Lan D (2015)

Li Q (2015)Li J (2012)

Ma C (2013)Ou M (2008)Pang G (2010)Sun D (2018)Wang X (2008)Wang X (2010)Xie D (2006)Xing B (2013)Xiong B (2009)Xu G (2012)Yu M (2016)Zhang W (2018)

Total

5930

11640

108403032403156525046424745

35

899

Events

5426

1103399242628372749464141344244

34

795

Total

5928

10040

108403032403149525039424745

35

867

Events

3718

892192181624301637302530233432

27

599

Weight(%)

6.14.26.69.43.99.02.73.45.56.43.46.75.24.26.44.16.36.6

100.0

M-H, random, 95% CI

1.46 [1.18, 1.80]1.35[0.99, 1.84]1.26 [1.04, 1.52]1.07 [0.98, 1.16]1.57 [1.13, 2.18]1.08 [0.98, 1.19]1.33 [0.87, 2.04]1.63 [1.13, 2.34]1.17 [0.92, 1.48]1.23 [1.01, 1.51]1.69 [1.17, 2.44]1.16 [0.96, 1.40]1.53 [1.19, 1.97]1.64 [1.21, 2.23]1.16 [0.95, 1.41]1.48 [1.08, 2.02]1.24 [1.01, 1.51]1.38 [1.14, 1.66]

1.29 [1.19, 1.40]Total (95% CI)Total events

Test for overall effect: Z = 6.17 (P < 0.00001)Heterogeneity: tau2 = 0.02, chi2 = 46.65, df = 17 (P = 0.0001); I2 = 64%

Figure 4: Forest plot of the clinical efficacy in ECG of phytochemical medicines containing tanshinol and ligustrazine in the treatment ofstable angina.

Study or subgroup Experimental Control Risk ratioRisk ratio

Cao Y (2017)

M-H, fixed, 95% CI

0.5 0.7Favours (control) Favours (experimental)

1 21.5

Chen X (2017)Ding X (2016)Han J (2016)He L (2017)

Hua Z (2014)Hu L (2012)

Jia Z (2017)Lan D (2015)

Li P (2017)Li Q (2015)

Li J (2012)

Liu L (2011)Ma C (2013)Ma T (2016)Ou M (2008)Pang G (2010)Sun D (2018)Tian H (2008)Wang X (2008)Wang X (2010)

Xie D (2006)Xi H (2017)

Xing B (2013)Xiong B (2009)Xu G (2012)Yu M (2016)Zhang W (2018)

Total (95% CI)Total events

Test for overall effect: Z = 11.60 (P < 0.00001)Heterogeneity: chi2 = 47.37, df = 27 (P = 0.009); I2 = 43%

Total

59

1276

303035303538

1164040

108304052303240

40

42

5250

4745

46

323156

50

Events

5644262834283437

1123537

100293345263038

38

36

4844

4143

1173

42

292951

Total

59

28

100

30

1242

39

303035

3538

4040

1083040

49

52303240

405250

424745

31

50

Events

48

919

21222921252991222894222633162429

31

24

3829

3330

32

232340

36

Weight(%)

5.13.93.92.32.43.12.32.73.1

10.52.43.0

10.12.42.83.51.72.63.12.52.54.63.34.13.13.72.63.53.2

100.0

M-H, fixed, 95% CI

1.17 [1.02, 1.34]1.22 [1.00, 1.49]1.24 [0.94, 1.63]1.27 [1.01, 1.61]1.17 [1.00, 1.38]1.24 [0.98, 1.57]1.36 [1.09, 1.69]1.28 [1.06, 1.53]1.06 [0.99, 1.14]1.59 [1.17, 2.16]1.32 [1.06, 1.65]1.06 [0.97, 1.16]1.32 [1.05, 1.65]1.27 [0.97, 1.66]1.36 [1.08, 1.72]1.63 [1.13, 2.34]1.25 [1.00, 1.56]1.31 [1.07, 1.61]1.18 [0.94, 1.48]1.26 [1.00, 1.58]1.12 [0.95, 1.30]1.23 [1.02, 1.47]1.26 [1.05, 1.52]1.52 [1.17, 1.96]1.11 [0.94, 1.32]1.50 [1.12, 2.00]1.24 [1.00, 1.54]1.43 [1.15, 1.78]

1.24 [1.20, 1.29]

Figure 3: Forest plot of the clinical efficacy in symptoms of phytochemical medicines containing tanshinol and ligustrazine in the treatmentof stable angina.

Evidence-Based Complementary and Alternative Medicine 7

conventional treatments were used in different controlgroups. ,erapies in the intervention group were based onthe control group; different therapies make the efficacy hardto be assessed.

,e high risk of bias of the included studies makes themethodological quality for this finding low.,ere are severallimitations to this systematic review. First, for most of theincluded studies, the methods for randomization, allocationconcealment, and blinding were not reported clearly. Sec-ond, in the 28 included studies, only 8 studies had samplesizes greater than 100 patients, and the small sample sizes inmost studies made meaningful conclusions difficult to bedrawn. ,ird, clinical efficacy was the main outcomemeasurement for most studies, but a bias from the physi-cians may decrease the reliability and validity of the studies.Fourth, all the studies were published in China, which maylimit the generalization of the findings.

5. Conclusion

In conclusion, this meta-analysis included 28 studies thatused phytochemical medicines containing tanshinol andligustrazine in the treatment of stable angina, and the resultssupported their clinical application. However, the studiesanalyzed to date are of relatively low quality. More rigorousRCTs with large sample sizes are needed to further evaluatethe clinical efficacy and the adverse effects.

Abbreviations

RCTs: Randomized controlled trialsECG: ElectrocardiographyDCI: Danshen chuanxiongqin injectionSGI: Shenxiong glucose injectionDI: Danshen injectionLI: Ligustrazine injectionCIs: Confidence intervalsAEs: Adverse eventsTCR: Treatments in the control groupACE: Angiotensin-converting enzymeARBs: Angiotensin receptor blockersCES: Clinical efficacy in symptoms.

Data Availability

All data generated or analyzed during this study are includedin this published article and its supplementary informationfiles.

Additional Points

Highlights. (i) It was the first meta-analysis assessing theefficacy of phytochemical medicines containing tanshinoland ligustrazine in the treatment of stable angina. (ii) ,eclinical efficacy and safety of phytochemical medicinescontaining tanshinol and ligustrazine in the treatment ofstable angina were comprehensively assessed. (iii) ,e ef-ficacy of phytochemical medicines containing tanshinol andligustrazine in the treatment of stable angina needed to befurther evaluated.

Conflicts of Interest

,e authors declare that they have no conflicts of interest.

Authors’ Contributions

LG contributed to conception, acquisition, analysis, andinterpretation; TW contributed to acquisition, analysis, andinterpretation; JW contributed to interpretation; ZX con-tributed to acquisition and analysis; CJ contributed to ac-quisition and analysis; WW contributed to conception andinterpretation. All authors drafted manuscript, revisedmanuscript, gave final approval, and agreed to be ac-countable for all aspects of work ensuring integrity andaccuracy.

Acknowledgments

,is study was supported by China Postdoctoral ScienceFoundation (Grant no. 2019M650598), Fundamental Re-search Funds for the Central Universities (Grant no. 2019-JYB-JS-005), National Natural Science Foundation of China(Grant no. 81874514), and National Key Research andDevelopment Program of China (Grant no.2017YFC1700102).

Supplementary Materials

File name: Appendix table. Title of data: summary table ofthe constituents of the 28 included studies. Description ofdata: statements of the constituents of the included studies.(Supplementary Materials)

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